Combinatorial responses of fungal pathogens to their human hosts: an Integrative Systems Biology approach

生物系统不断受到各种各样的外部刺激和挑战。其中许多是不断变化的，为了生存，生物体必须对每一种新的环境做出适当的反应。然而，科学家很难研究如此复杂的扰动，因此通常研究人员一次只关注一个刺激。虽然这已经产生了重要的生物学见解，但为了取得进一步的进展，我们需要开发研究几种同时扰动组合的方法。单靠传统实验技术是无法做到这一点的。这些需要数学和计算建模方法的补充，这些方法可以整合来自不同实验的数据，揭示隐藏的模式，解释明显矛盾的结果，并提出新的生物学假设。这种跨学科的研究被称为系统生物学。最近在英国建立了一些中心来支持综合系统生物学。该项目涉及伦敦帝国理工学院的其中一个中心（CISBIC），其重点是病原体与其宿主之间的相互作用。CISBIC将与阿伯丁大学合作，从而扩大CISBIC研究病原体的范围，加强两个机构现有的合作，并帮助将阿伯丁快速增长的系统生物学小组整合到英国和欧洲社区。我们打算应用综合系统生物学技术来了解病原真菌在入侵人类宿主时如何对不同压力组合做出反应。我们将集中在人类的主要真菌病原体，白色念珠菌和光念珠菌。它们经常引起口腔和阴道感染（鹅口疮），并对移植和癌症患者造成危及生命的血液和内脏感染。当这些病原体侵入病人体内时，免疫系统通常会采取各种对抗措施来杀死病原体。对于微生物来说，这些应对措施本质上相当于环境压力，因此它激活了将这些压力造成的损害最小化的策略。病原体的成功取决于它如何很好地抵消这些压力以击败宿主的防御。我们将研究这些致病性念珠菌物种如何对它们在人类宿主中经历的压力组合作出反应。我们将首先单独研究三种压力中的每一种，然后使用实验和模型的混合来探索当两种不同的压力一起施加时，这些反应是如何不同的。然后，我们将使用这些信息来预测并验证当三种应力同时遇到时会发生什么。最后，我们将评估我们对这两种致病物种的应激反应的理解在多大程度上可以用来预测相关物种的反应，这些物种的实验信息较少。这是一个重要的生物学问题/该项目将提供关于生物系统如何对环境信号组合作出反应的宝贵信息，并增加我们对病原微生物如何与人类相互作用的理解。

Biological systems are constantly subjected to a wide variety of external stimuli and challenges. Many of these change continuously and in order to survive the organism must respond appropriately to each new set of circumstances. It is however difficult for scientists to study such complex perturbations and so typically researchers have focused on one stimulus at a time. Whilst this has yielded major biological insights, to make further progress we need to develop approaches to studying combinations of several simultaneous perturbations. This cannot be done using conventional experimental techniques alone. These need to be supplemented by mathematical and computational modelling methods, which can integrate data from different experiments, reveal hidden patterns, explain apparently contradictory results and suggest new biological hypotheses. This type of interdisciplinary research is called Systems Biology. Recently a number of centres have been established in the UK to champion Integrative Systems Biology. This project involves one of these centres (CISBIC) at Imperial College London, whose focus is on the interaction between pathogens and their hosts. CISBIC will be partnered by Aberdeen University, thereby extending the range of pathogens studied at CISBIC, strengthening the two institutions existing collaborations and helping to integrate the rapidly growing systems biology group at Aberdeen into the UK and European community. We intend to apply Integrative Systems Biology techniques to understanding how pathogenic fungi respond to the combinations of different stresses they encounter when they invade a human host. We shall focus on the major fungal pathogens of humans, Candida albicans and Candida glabrata. They cause frequent oral and vaginal infections (thrush) and cause life-threatening infections of the bloodstream and internal organs in transplant and cancer patients. When such pathogens invade a patient, the immune system normally responds with a variety of counter-measures designed to kill the pathogen. For the microbe these counter-measures are essentially equivalent to environmental stresses, and hence it activates strategies to minimize the damage done by these stresses. The success of the pathogen depends on how well it counteracts these stresses to defeat the host's defences. We will study how these pathogenic Candida species respond to the combinations of stresses they experience in their human host. We will start by investigating each of three stresses in isolation and then use a mixture of experiments and models to explore how these responses differ when two different stresses are applied together. We will then use this information to predict and then validate what happens when the three stresses are encountered simultaneously. Finally, we will evaluate the extent to which our understanding of stress responses in these two pathogenic species can be used to predict the responses of related species for which less experimental information is available. This is an important biological question / this project will provide invaluable information about how biological systems in general respond to combinations of environmental signals as well as increasing our understanding of how pathogenic microbes interact with humans.